Elsevier

Atherosclerosis

Volume 277, October 2018, Pages 483-492
Atherosclerosis

Review article
Familial hypercholesterolemia treatments: Guidelines and new therapies

https://doi.org/10.1016/j.atherosclerosis.2018.06.859Get rights and content

Highlights

  • Familial hypercholesterolemia (FH) is underdiagnosed and undertreated.

  • Current guidelines clearly indicate LDL-C goal for FH subjects.

  • Combination of available lipid-lowering therapies improves the management of FH.

  • Novel emerging therapies for FH are currently under development.

Abstract

Familial hypercholesterolemia (FH) is a genetic disorder resulting from mutations in genes encoding proteins involved in the metabolism of low density lipoproteins (LDL) and characterized by premature cardiovascular disease due to the exposure to high levels of LDL-cholesterol (LDL-C) from birth. Thus, the early identification of FH subjects, followed by appropriate treatment is essential to prevent or at least delay the onset of cardiovascular events. However, FH is largely underdiagnosed; in addition, FH patients are frequently not adequately treated, despite the availability of several pharmacological therapies to significantly reduce LDL-C levels. Current guidelines recommend LDL-C targets for FH (either heterozygotes [HeFH] or homozygotes [HoFH]) <100 mg/dL (<2.6 mmol/L) for adults or <70 mg/dL (<1.8 mmol/L) for adults with CHD or diabetes, and <135 mg/dL (<3.5 mmol/L) for children. With the pharmacological options now available, which include statins as a first approach, ezetimibe, and the recently approved monoclonal antibodies targeting PCSK9, the guideline recommended LDL-C target levels can be achieved in the majority of heterozygous FH subjects, while for the most severe forms of homozygous FH, the addition of therapies such as lomitapide either with or without apheresis may be required.

Introduction

Familial hypercholesterolemia (FH) is a genetic disorder characterized by very high levels of circulating low density lipoprotein cholesterol (LDL-C) from birth. This does result in the fast development of atherosclerosis with detrimental outcomes such as myocardial infarction and death occurring early in life in patients with FH, especially in those who are not or inadequately treated [[1], [2], [3], [4]]. Despite several effective cholesterol-lowering drugs now being available, a main gap in the management of this disease is the lack of early detection and appropriate pharmacological intervention of FH subjects. In fact, the most severe forms, such as homozygous FH, generally exhibit unambiguous physical signs from the childhood; in contrast, less severe forms of FH may remain hidden until the occurrence of the first cardiovascular event. Thus, the early identification of these subjects is crucial to reduce the burden of cholesterol exposure and the incidence of cardiovascular events.

Genetic defects in several genes involved in LDL metabolism may cause FH; mutations in the LDLR gene, encoding for the LDL receptor (LDLR) are the most common cause of FH, but mutations in the APOB gene and gain-of-function (GOF) mutations in the PCSK9 gene can also result in the FH phenotype [[5], [6], [7]]. A rare recessive form of hypercholesterolemia (autosomal recessive hypercholesterolemia, ARH) is caused by the loss-of-function mutations in the LDLRAP1 gene (encoding for a protein that promotes the internalization of LDLR/LDL complex) [8,9]. However, among subjects with a clinical diagnosis of FH, only 40–80%, depending on the criteria used, exhibit a mutation in one of the classical genes causative of FH, which suggests that a relatively high proportion of “mutation-negative” FH patients are likely to have a polygenic cause underlying their marked hypercholesterolemia [10,11].

The heterozygous form of FH (HeFH) has a prevalence of ∼1/500 to 1/200 in the general population and is characterized by a 2–3 fold increase of LDL-C levels and the occurrence of coronary heart disease (CHD) before age 55 (60 for women) [1,2,12]; the homozygous form (HoFH) is rarer, with a prevalence of ∼1/160,000–1/300,000, and HoFH patients are generally characterized by an even more severe LDL-C level phenotype. This greater cholesterol burden does result in the onset of extremely premature cardiovascular disease, with HoFH patients who suffer from a myocardial infarction well before their 10th year of age [2], particularly in HoFH patients who carry two receptor-negative mutations [2,5]. Subjects carrying mutations in APOB or PCSK9 genes generally exhibit a milder phenotype [6,13].

The diagnosis of FH can be based either on clinical criteria or genetic testing; the last provides a definitive diagnosis of FH, but there are some patients with clinical diagnosis of FH in whom no mutation can be identified in the genes classically associated to this condition, suggesting the involvement of unknown genes or a polygenic cause. However, a positive genetic test allows one to discriminate a FH subject from a “normal” hypercholesterolemic individual on the one hand [14], and on the other aids in the identification of FH among relatives. Due to the high number of possible mutations causing FH and due to the possible involvement of additional genes, the phenotype of FH is highly variable, and subjects carrying the same mutation may exhibit profoundly different lipid and clinical profiles as well as different responses to the same pharmacological treatment; in addition, subjects with HoFH may present LDL-C levels well below those expected for this condition and thus may not be recognized.

Section snippets

Guidelines for the management of familial hypercholesterolemia

Based on a prevalence of 1/200-1/500, it can be estimated that there are between 14 and 34 million individuals having FH worldwide, but in most countries less than 1% are diagnosed (with some exceptions) [1]. Another major key point is that subjects with FH have an at least 10-fold increase risk of CHD, which may manifest early in life, and the risk remains high even among patients treated with statins, which suggests that they are treated with therapies that are inadequate (low dose, late in

Statins

Statin therapy represents the first pharmacological approach for the management of hypercholesterolemia in FH patients, and current guidelines recommend that adults are treated with the maximal tolerated dose of a high potency statin [1]. In most cases, however, statin monotherapy is insufficient to achieve the recommended LDL-C levels.

Given the mechanism of action of statins, which exert their lipid-lowering effect partly by increasing the hepatic expression of LDLR, it is expected that

Conclusions

Current guidelines strongly support treatment of FH with goals of 100 (2.56 mmol/L) and 70 mg/dL (1.86 mmol/L) according to the risk levels. Up to 3 decades ago, the treatment of severe hypercholesterolemia in FH was a clinical dilemma. The availability of statins and later on of other pharmacological interventions has produced a dramatic shift in our capability of controlling LDL levels even in homozygous patients, with a few exceptions in which apheresis is still required. The most important

Conflicts of interest

F.J.R. has received research grants from Amgen, Sanofi, Regeneron Pharmaceuticals, Inc. and the Medicines Company, has served on and received honoraria for a Speakers Bureau and consultant/advisory boards for Amgen, Sanofi, Regeneron Pharmaceuticals, Inc., and the Medicines Company.

G.K.H. reports consulting and/or lecture fees from Amgen Inc, Regeneron/Sanofi, and Pfizer related to PCSK9 inhibitors, and institutional research funding related to PCSK9 inhibitor clinical trials from Amgen Inc,

Financial support

The work of ALC is supported by: Fondazione Cariplo 2015-0524 and 2015-0564; H2020 REPROGRAM PHC-03-2015/667837-2; ERA-NET ER-2017-2364981.

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